Targeting mTOR Pathway in Hepatocellular Carcinoma

The mammalian target of rapamycin (mTOR) pathway occupies a central position in the regulation of cell growth, metabolism and survival, functions that are frequently subverted in hepatocellular carcinoma (HCC). Deregulation of upstream regulators such as PI3K, AKT and the tuberous sclerosis complex (TSC1/2) fosters aberrant activation of mTOR complexes, notably mTORC1, which in turn drives protein synthesis, lipid biogenesis and glycolytic metabolism. These metabolic and proliferative adaptations underpin tumour initiation, progression and therapeutic resistance in HCC. The translation of mTOR inhibition into clinical practice has been propelled by rapamycin analogues and ATP‐competitive inhibitors, yet monotherapy has yielded modest benefits owing to adaptive feedback loops and compensatory pathways. Contemporary strategies aim to overcome these hurdles through combination regimens—pairing mTOR inhibitors with tyrosine kinase inhibitors or immune modulators—and through companion diagnostics that predict pathway activation status, thereby enabling patient stratification. Non‐invasive imaging biomarkers and genomics‐guided profiling are also emerging to identify suitable candidates for targeted therapy. Collectively, these advances underscore the global significance of mTOR as both a therapeutic target and a hub for integrating diverse oncogenic signals in HCC, offering new avenues for precision medicine in this common and often lethal malignancy.

Research from Nature Portfolio

A seminal study employing a murine model demonstrated that concurrent activation of AKT and c-Met precipitates rapid HCC development via an mTORC1–FASN axis. Genetic ablation of fatty acid synthase (FASN) in this context fully abrogated tumour formation, highlighting de novo lipogenesis as a non‐redundant effector downstream of mTORC1. These findings illuminate the dependency of a biologically aggressive HCC subset on an mTORC1‐driven lipogenic programme, supporting dual inhibition of mTORC1 signalling and lipid metabolism as a rational therapeutic strategy.

Targeting mTOR Pathway in Hepatocellular Carcinoma publication trend

The graph below shows the total number of articles in targeting mtor pathway in hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

mTOR: Central serine/threonine kinase integrating nutrient and growth factor signals to regulate cell growth and metabolism.

mTORC1: Rapamycin-sensitive complex of mTOR that controls protein synthesis, lipid biosynthesis and autophagy.

mTORC2: Rapamycin-insensitive complex of mTOR that modulates cell survival and cytoskeletal organisation.

TSC: Tuberous sclerosis complex (TSC1 and TSC2), a key upstream inhibitor of mTORC1.

FASN: Fatty acid synthase, enzyme responsible for de novo lipogenesis essential for tumour proliferation.

Ferroptosis: Iron-dependent form of regulated cell death marked by lipid peroxidation.

Radiomics: Extraction and analysis of quantitative features from medical images to characterise tumour phenotype.

Sorafenib: Multikinase inhibitor used as first-line therapy in advanced hepatocellular carcinoma.

4EBP1: Eukaryotic initiation factor 4E-binding protein 1, a regulator of cap-dependent translation downstream of mTORC1.

References

1. Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice. Scientific Reports (2016).
2. TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M. Journal of Clinical Investigation (2024).
3. Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment. Cell Death & Disease (2025).
4. Application of multi-modality MRI-based radiomics in the pre-treatment prediction of RPS6K expression in hepatocellular carcinoma. Molecular Biomedicine (2023).